Chemical Structure Information at the Bench: A New Integrated Approach

AbstractPrediction of pharmacokinetic profiles of new chemical entities is essential in drug development to minimize the risks of potential withdrawals. The excretion of unchanged compounds by the kidney constitutes a major route in drug elimination and plays an important role in pharmacokinetics. Herein, we created in silico prediction models of the fraction of drug excreted unchanged in the urine (fe) and renal clearance (CLr), with datasets of 411 and 401 compounds using freely available software; notably, all models require chemical structure information alone. The binary classification model for fe demonstrated a balanced accuracy of 0.74. The two-step prediction system for CLr was generated using a combination of the classification model to predict excretion-type compounds and regression models to predict the CLr value for each excretion type. The accuracies of the regression models increased upon adding a descriptor, which was the observed and predicted fraction unbound in plasma (fu,p); 78.6% of the samples in the higher range of renal clearance fell within 2-fold error with predicted fu,p value. Our prediction system for renal excretion is freely available to the public and can be used as a practical tool for prioritization and optimization of compound synthesis in the early stage of drug discovery.

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The Chemical Structure Association Trust

Chemistry International ◽

10.1515/ci-2016-0206 ◽

2016 ◽

Vol 38 (2) ◽

Author(s):

Bonnie Lawlor

Keyword(s):

Chemical Structure ◽

Scientific Discovery ◽

Research Work ◽

50Th Anniversary ◽

The United States ◽

Chemical Information ◽

Structure Information ◽

Chemical Structures ◽

Grant Program ◽

Structure Association

AbstractThe Chemical Structure Association Trust (CSA Trust) is an internationally-recognized, registered charity that promotes and supports the advancement of scientific discovery through the application of computer technologies in the management and analysis of chemical structure information. In support of its Charter, the Trust provides grants specifically to nurture young scientists, ages thirty-five or younger, who have demonstrated excellence in research related to the storage, retrieval, and analysis of chemical structures, reactions, and compounds. Since its inception in 1988, almost one hundred students and researchers worldwide have benefited from travel bursaries and the CSA Trust Grant Program to further their education and research work, but the organization has a rich history that predates the formalization of its charity status. Its roots were planted half a century ago in 1965, when the Chemical Notation Association (CNA) was formed in the United States. It has been an interesting journey from the CNA to the CSA Trust and I have been blessed to have been a part of it almost from the beginning, along with other members of the American Chemical Society’s Division of Chemical Information. In honor of the organization’s 50th Anniversary, I’d like to give a brief overview of its past and its present activities.

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